Chromosome 1p36 deletion syndrome

Summary

Chromosome 1p36 deletion syndrome (MONDO:0011929) is a disease with 9 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-5 / 10 000 (United States) [Orphanet-validated]
• Cohort genes: 9
• ClinVar variants: 15
• Phenotypes (HPO): 99
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	15	United States	Validated
Prevalence at birth	1-5 / 10 000	15	United States	Validated

Signs & symptoms

Clinical features (HPO)

99 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000307	Pointed chin	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001344	Absent speech	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001773	Short foot	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0011228	Horizontal eyebrow	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0100490	Camptodactyly of finger	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000534	Abnormal eyebrow morphology	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0008499	High hypermetropia	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0100716	Self-injurious behavior	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000055	Abnormality of female external genitalia	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000107	Renal cyst	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 1p36 deletion syndrome
Mondo ID	MONDO:0011929
MeSH	C535362
OMIM	607872
Orphanet	1606
DOID	DOID:0060410
NCIT	C74983
SNOMED CT	699306003
UMLS	C1842870
MedGen	334629
GARD	0006082
Is cancer (heuristic)	no

Also known as: 1p telomere deletion syndrome · 1p36 deletion syndrome · 1p36 microdeletion syndrome · chromosome 1p36 deletion syndrome, distal, isolated cases · Del(1)(p36) · deletion 1p36 · deletion 1pter · monosomy 1p36 · monosomy 1pter · subtelomeric 1p36 deletion

Data availability: 15 ClinVar variants · 47 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › chromosomal disorder › syndrome caused by partial chromosomal deletion › partial deletion of chromosome 1 › partial deletion of the short arm of chromosome 1 › chromosome 1p36 deletion syndrome

Related subtypes (4): chromosome 1p32-p31 deletion syndrome, 1p21.3 microdeletion syndrome, 1p35.2 microdeletion syndrome, chromosome 1p35 deletion syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

13 pathogenic, 1 not provided, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684638	Single allele	ACAP3	Pathogenic	criteria provided, single submitter
1703627	GRCh37/hg19 1p36.33-36.31(chr1:849466-5625566)	ACAP3	Pathogenic	no assertion criteria provided
1703628	GRCh37/hg19 1p36.33-36.32(chr1:849466-4183006)	ACAP3	Pathogenic	no assertion criteria provided
2501007	GRCh37/hg19 1p36.33-36.32(chr1:1-2580976)x1	ACAP3	Pathogenic	criteria provided, single submitter
625766	GRCh37/hg19 1p36.33-36.31(chr1:823964-6828363)	ACAP3	Pathogenic	criteria provided, single submitter
625768	GRCh37/hg19 1p36.33-36.32(chr1:568708-2567832)	ACAP3	Pathogenic	criteria provided, single submitter
1703625	GRCh37/hg19 1p36.31-36.23(chr1:6250285-7943864)	ACOT7	Pathogenic	no assertion criteria provided
2574677	GRCh37/hg19 1p36.33-36.31(chr1:1957148-6553454)	ACOT7	Pathogenic	no assertion criteria provided
666432	GRCh37/hg19 1p36.33-36.32(chr1:1723651-3444846)x1	ACTRT2	Pathogenic	criteria provided, single submitter
974581	Single allele	C1orf174	Pathogenic	criteria provided, single submitter
2446820	NC_000001.10:g.4481271_20530242del	CASP9	Pathogenic	criteria provided, single submitter
625767	GRCh37/hg19 1p36.33-36.32(chr1:568708-3662949)	MEGF6	Pathogenic	criteria provided, single submitter
1341993	GRCh37/hg19 1p36.33-36.23(chr1:834101-7930605)x1	TMEM240	Pathogenic	criteria provided, single submitter
875052	NM_005529.7(HSPG2):c.337G>A (p.Glu113Lys)	HSPG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1177499	GRCh37/hg19 1p36.32-36.23(chr1:2420003-8155935)x1	NOL9	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM240	Orphanet:98773	Spinocerebellar ataxia type 21
HSPG2	Orphanet:1606	1p36 deletion syndrome
HSPG2	Orphanet:1865	Dyssegmental dysplasia, Silverman-Handmaker type
HSPG2	Orphanet:800	Schwartz-Jampel syndrome

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASP9	HGNC:1511	ENSG00000132906	P55211	Caspase-9	clinvar
ACAP3	HGNC:16754	ENSG00000131584	Q96P50	Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3	clinvar
ACTRT2	HGNC:24026	ENSG00000169717	Q8TDY3	Actin-related protein T2	clinvar
ACOT7	HGNC:24157	ENSG00000097021	O00154	Cytosolic acyl coenzyme A thioester hydrolase	clinvar
TMEM240	HGNC:25186	ENSG00000205090	Q5SV17	Transmembrane protein 240	clinvar
NOL9	HGNC:26265	ENSG00000162408	Q5SY16	Polynucleotide 5’-hydroxyl-kinase NOL9	clinvar
C1orf174	HGNC:27915	ENSG00000198912	Q8IYL3	UPF0688 protein C1orf174	clinvar
MEGF6	HGNC:3232	ENSG00000162591	O75095	Multiple epidermal growth factor-like domains protein 6	clinvar
HSPG2	HGNC:5273	ENSG00000142798	P98160	Basement membrane-specific heparan sulfate proteoglycan core protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASP9	Caspase-9	Involved in the activation cascade of caspases responsible for apoptosis execution.
ACAP3	Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3	GTPase-activating protein for the ADP ribosylation factor family.
ACOT7	Cytosolic acyl coenzyme A thioester hydrolase	Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.
NOL9	Polynucleotide 5’-hydroxyl-kinase NOL9	Polynucleotide kinase that can phosphorylate the 5’-hydroxyl groups of single-stranded and double-stranded RNA and DNA substrates.
HSPG2	Basement membrane-specific heparan sulfate proteoglycan core protein	Integral component of basement membranes.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	3.2×	0.539
Enzyme (other)	2	2.7×	0.539
Scaffold/PPI	1	1.9×	0.553
Other/Unknown	5	1.0×	0.641

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASP9	Enzyme (other)	yes	3.4.22.62	Pept_C14_p20, CARD, Pept_C14_p10
ACAP3	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt
ACTRT2	Other/Unknown	no		Actin, Actin/actin-like_CS, ATPase_NBD
ACOT7	Enzyme (other)	yes	3.1.2.2	Thioestr_dom, HotDog_dom_sf, HOTDOG_ACOT
TMEM240	Other/Unknown	no		TMEM240
NOL9	Other/Unknown	no		P-loop_NTPase, CLP1_P, Clp1/Grc3
C1orf174	Other/Unknown	no		UPF0688
MEGF6	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
HSPG2	Antibody/Immunoglobulin	yes		Laminin_IV, SEA_dom, EGF

Expression context

Cohort genes with no expression data: 0.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
adrenal tissue	1
left ovary	1
right uterine tube	1
cerebellar cortex	1
left testis	1
primordial germ cell in gonad	1
right testis	1
lateral nuclear group of thalamus	1
prefrontal cortex	1
right frontal lobe	1
cerebellum	1
medial globus pallidus	1
nipple	1
tibialis anterior	1
gingival epithelium	1
oocyte	1
secondary oocyte	1
ascending aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASP9	290	ubiquitous	marker	adrenal tissue, right uterine tube, left ovary
ACAP3	221	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ACTRT2	31	tissue_specific	marker	left testis, right testis, primordial germ cell in gonad
ACOT7	264	ubiquitous	marker	lateral nuclear group of thalamus, prefrontal cortex, right frontal lobe
TMEM240	129	broad	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum
NOL9	287	ubiquitous	marker	tibialis anterior, medial globus pallidus, nipple
C1orf174	281	ubiquitous	marker	oocyte, secondary oocyte, gingival epithelium
MEGF6	205	ubiquitous	marker	right coronary artery, descending thoracic aorta, ascending aorta
HSPG2	271	ubiquitous	marker	saphenous vein, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASP9	4,140
HSPG2	2,463
ACTRT2	2,113
NOL9	1,975
ACOT7	1,589
ACAP3	927
MEGF6	859
C1orf174	650
TMEM240	326

Structural data

PDB: 4 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASP9	P55211	11
NOL9	Q5SY16	2
HSPG2	P98160	2
ACOT7	O00154	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTRT2	Q8TDY3	93.42
ACAP3	Q96P50	76.31
MEGF6	O75095	70.56
C1orf174	Q8IYL3	61.92
TMEM240	Q5SV17	58.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 9 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of caspases through apoptosome-mediated cleavage	1	475.8×	0.020	CASP9
SMAC (DIABLO) binds to IAPs	1	407.9×	0.020	CASP9
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	407.9×	0.020	CASP9
SMAC, XIAP-regulated apoptotic response	1	407.9×	0.020	CASP9
Formation of apoptosome	1	356.9×	0.020	CASP9
Caspase activation via extrinsic apoptotic signalling pathway	1	356.9×	0.020	CASP9
Cytochrome c-mediated apoptotic response	1	317.2×	0.020	CASP9
Caspase activation via Dependence Receptors in the absence of ligand	1	285.5×	0.020	CASP9
Regulation of the apoptosome activity	1	259.6×	0.020	CASP9
Apoptotic factor-mediated response	1	219.6×	0.020	CASP9
AKT phosphorylates targets in the cytosol	1	203.9×	0.020	CASP9
Defective EXT2 causes exostoses 2	1	203.9×	0.020	HSPG2
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	203.9×	0.020	HSPG2
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	167.9×	0.021	HSPG2
Attachment and Entry	1	150.3×	0.021	HSPG2
Defective B4GALT7 causes EDS, progeroid type	1	142.8×	0.021	HSPG2
Defective B3GAT3 causes JDSSDHD	1	142.8×	0.021	HSPG2
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	142.8×	0.021	HSPG2
HS-GAG degradation	1	124.1×	0.022	HSPG2
Respiratory syncytial virus (RSV) attachment and entry	1	124.1×	0.022	HSPG2
Initiation of coagulation cascade	1	119.0×	0.022	HSPG2
Constitutive Signaling by AKT1 E17K in Cancer	1	105.7×	0.022	CASP9
Glycosaminoglycan-protein linkage region biosynthesis	1	98.5×	0.022	HSPG2
Laminin interactions	1	95.2×	0.022	HSPG2
Mitochondrial Fatty Acid Beta-Oxidation	1	95.2×	0.022	ACOT7
PI3K/AKT Signaling in Cancer	1	92.1×	0.022	CASP9
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	89.2×	0.022	CASP9
HS-GAG biosynthesis	1	86.5×	0.022	HSPG2
NOD1/2 Signaling Pathway	1	79.3×	0.023	CASP9
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.023	HSPG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
long-chain fatty-acyl-CoA catabolic process	1	3370.4×	0.005	ACOT7
response to indole-3-methanol	1	3370.4×	0.005	CASP9
palmitic acid biosynthetic process	1	3370.4×	0.005	ACOT7
cleavage in ITS2 between 5.8S rRNA and LSU-rRNA of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	1685.2×	0.007	NOL9
leukocyte apoptotic process	1	1685.2×	0.007	CASP9
negative regulation of synaptic transmission, cholinergic	1	1123.5×	0.007	HSPG2
glial cell apoptotic process	1	1123.5×	0.007	CASP9
response to hypoxia	2	38.3×	0.007	CASP9, HSPG2
medium-chain fatty-acyl-CoA catabolic process	1	674.1×	0.009	ACOT7
medium-chain fatty acid biosynthetic process	1	561.7×	0.009	ACOT7
response to anesthetic	1	561.7×	0.009	CASP9
response to cobalt ion	1	481.5×	0.010	CASP9
coenzyme A biosynthetic process	1	306.4×	0.013	ACOT7
fibroblast apoptotic process	1	306.4×	0.013	CASP9
circulatory system development	1	280.9×	0.013	HSPG2
fatty acid catabolic process	1	259.3×	0.013	ACOT7
maturation of 5.8S rRNA	1	210.7×	0.015	NOL9
positive regulation of execution phase of apoptosis	1	168.5×	0.017	CASP9
epithelial cell apoptotic process	1	168.5×	0.017	CASP9
signal transduction in response to DNA damage	1	160.5×	0.017	CASP9
protein localization to synapse	1	153.2×	0.017	HSPG2
acyl-CoA metabolic process	1	140.4×	0.017	ACOT7
platelet formation	1	140.4×	0.017	CASP9
animal organ regeneration	1	120.4×	0.019	HSPG2
cellular response to dexamethasone stimulus	1	116.2×	0.019	CASP9
regulation of neuron projection development	1	86.4×	0.024	ACAP3
negative regulation of cell adhesion	1	76.6×	0.026	HSPG2
intrinsic apoptotic signaling pathway	1	71.7×	0.027	CASP9
embryo implantation	1	70.2×	0.027	HSPG2
intrinsic apoptotic signaling pathway in response to DNA damage	1	64.8×	0.028	CASP9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 9

Druggability breadth: 3 of 9 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASP9	0	0
ACAP3	0	0
ACTRT2	0	0
ACOT7	0	0
TMEM240	0	0
NOL9	0	0
C1orf174	0	0
MEGF6	0	0
HSPG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CASP9	65	Binding:63, Functional:2
HSPG2	2	Binding:2
ACOT7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASP9	3.4.22.62	caspase-9
ACOT7	3.1.2.2, 3.1.2.20	palmitoyl-CoA hydrolase, acyl-CoA hydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	CASP9, ACOT7, HSPG2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	ACAP3, ACTRT2, TMEM240, NOL9, C1orf174, MEGF6

Undrugged target profiles

9 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CASP9	65	—
ACAP3	0	—
ACTRT2	0	—
ACOT7	1	—
TMEM240	0	—
NOL9	0	—
C1orf174	0	—
MEGF6	0	—
HSPG2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)